Lymphatic filariasis is a mosquito-borne disease that is debilitating, horribly disfiguring, and affects an estimated 120 million people throughout the tropics. It is caused by filarial nematodes (Wuchereria bancrofti and Brugia malayi) that inhabit the lymphatic system. To perpetuate their life cycle, inseminated adult female worms produce millions of microfilariae (mf) that enter the blood stream, in the hopes that some will be ingested by an appropriate mosquito vector. Indeed, the presence of sheathed mf in patient blood is a definitive diagnosis for lymphatic filariasis. Throughout most of their geographic range, W. bancrofti and B. malayi exhibit nocturnal periodicity - that is, the mf only become abundant in peripheral blood during the middle of the night. During the day, the mf become sequestered in the alveolar capillaries of the lungs and are virtually absent from peripheral blood, making them inaccessible not only to diagnostic clinicians but also to potential mosquito vectors. The mechanism of nocturnal periodicity has been a neglected area of research in recent decades and as a result, the pacemaker responsible for synchronizing the circadian rhythms of the mf with that of their human hosts has never been elucidated. Hypothesis: The primary host cue that regulates mf periodicity is the bioactive amine, melatonin, which is secreted into the blood stream from the pineal gland at a regular, circadian periodicity. To test this hypothesis, we will use a naturally-occurring avian system of filariasis with pronounced nocturnal periodicity (e.g., Chandlerella quiscali filarids in the Common Grackle). The specific aims to be tested are 1) to determine if endogenous melatonin secretion regulates the nocturnal periodicity of microfilarial parasites,and 2) to determine if melatonin receptor antagonists can be administered to microfilaremic hosts in order to de-synchronize the circadian rhythms of host and parasite and thereby prevent the ingestion of mf by mosquitoes. Significance: If mf are prevented from being ingested by mosquitoes, then the parasites within infected hosts will not be spread and further transmission of the disease will be halted. This R03 application is a proof-of-concept study that may lead to an entirely new therapeutic approach to block the transmission of lymphatic filariasis. PUBLIC HEALTH RELEVANCE: The work examines the phenomenon of nocturnal periodicity of filarial parasites from the perspective of hormonal control of host circadian rhythms. It may lead to a new therapeutic approach to block the transmission of lymphatic filariasis.